The role of the protein-RNA recognition code in neurodegeneration

Abstract

MicroRNAs are small endogenous RNAs that pair and bind to sites on mRNAs to direct post-transcriptional repression. However, there is a possibility that microRNAs directly influence protein structure and activity, and this influence can be termed post-translational riboregulation. This conceptual review explores the literature on neurodegenerative disorders. Research on the association between neurodegeneration and RNA-repeat toxicity provides data that support a protein-RNA recognition code. For example, this code explains why hnRNP H and SFPQ proteins, which are involved in amyotrophic lateral sclerosis, are sequestered by the (GGGGCC)n repeat sequence. Similarly, it explains why MNBL proteins and (CTG)n repeats in RNA, which are involved in myotonic dystrophy, are sequestered into RNA foci. Using this code, proteins involved in diseases can be identified. A simple protein BLAST search of the human genome for amino acid repeats that correspond to the nucleotide repeats reveals new proteins among already known proteins that are involved in diseases. For example, the (CAG)n repeat sequence, when transcribed into possible peptide sequences, leads to the identification of PTCD3, Rem2, MESP2, SYPL2, WDR33, COL23A1, and others. After confirming this approach on RNA repeats, in the next step, the code was used in the opposite manner. Proteins that are involved in diseases were compared with microRNAs involved in those diseases. For example, a reasonable correspondence of microRNA 9 and 107 with amyloid-β-peptide (Aβ42) was identified. In the last step, a miRBase search for micro-nucleotides, obtained by transcription of a prion amino acid sequence, revealed new microRNAs and microRNAs that have previously been identified as involved in prion diseases. This concept provides a useful key for designing RNA or peptide probes.

Keywords: Alzheimer’s disease; Huntington’s disease; Molecular recognition; Non-coding RNA; Parkinson’s disease; Prion diseases.

Fig. 1

Protein–RNA recognition code. CCA trinucleotide is recognised as two dinucleotides—two-letter code (P-CC, Q-CA), or each nucleotide is recognised separately—one-letter code (T-C, T-C, N-A). One-letter code—second nucleotide in codons; two-letter code—first two nucleotides in codons. 3D5A crystal structure which contain release factor 1 (RF1) interacting with tRNA, as example [27]

Fig. 2

Proteins sequestered into RNA foci (a–c); and the recognition of polyadenylation signal by polyadenylation factor subunit 2 (d WDR33). a H component of the heterogeneous nuclear RNP (hnRNP H), recognising toxic (GGGGCC)n repeat; b muscleblind-like protein 1 (MNBL1), recognising toxic (CTG)n repeat; c the heat shock transcription factor 1 (HSF1), recognising toxic (CAG)n repeat; and d WDR33 recognising polyadenylation signal

Fig. 3

Illustrated protein sequences that are recognised by a MIR34a, b MIR9, and c MIR107; and d cartoon of the Aβ42 fibril core, structure (5KK3)

Fig. 4

Illustrated protein sequences that are recognised by a MIR7, b MIR153-1, and c MIR221-3p

Fig. 5

Prion diseases. a Pathogenic mutations (red, [98]) shown in the sequence and crystal structure of human wild-type PrP^C (5YJ5), short important amino acid sequences can be transcribed into nucleotide sequences and searched via the online miRBase. b, c Illustrated protein sequences that are recognised by MIR361 and MIR146a respectively